FI70893C - REFERENCE TO ANALYTICAL ANTINFLAMMATORS WITH ANTIPYRETIC 1- (1,3-BENZODIOXOL-5-YL) -2-PYRROLIDINONE - Google Patents

Description

1 70893

This invention relates to the synthesis of a compound useful in medicine. The present invention relates to the synthesis of a compound useful in medicine.

We have found that a compound of formula (I), 1 ° (~ y * ° XN (I)

X

O-CII2, chemically named 1- (1,3-benzodioxol-5-yl) -pyrrolidinone, is valuable in medicine for the treatment or prevention of pain, inflammation or fever.

It has been found that the compound of formula (I), hereinafter referred to as "compound (I)", "active substance" or "active compound", has an analgesic effect ranging from mild to quite intense. As an analgesic, compound (I) is similar to morphine or codeine, but superior to aspirin or acetaminophen, as seen in the trypsin assay and the hot plate assay. However, the analgesic mode of action of Compound (I) is likely to be different from that of morphine or codeine, as nalaxone does not inhibit its analgesic effect and does not bind to morphine receptors. Thus, the compound is not narcotic. The duration of the analgesic effect is significantly longer with compound (I) than with codeine or morphine.

Compound (I) has also been found to have a potent, long-lasting acute anti-inflammatory effect in rat-70703 Ia, as shown by the carrageenan pleurisy test (Vinegar et al., Proc. Soc. Exp. Biol. Med. 151, 556, (1976)). Compound (I) resembles acetaminophen in its acute anti-inflammatory effect, but its anti-inflammatory effect has been found to be stronger and longer lasting at comparable dose levels.

Compound (I), like acetaminophen, has been found to have an antipyretic effect, as can be demonstrated in an experiment inducing fever in rats on yeast (Khalili-10 Varasteh et al., Arch. Int. Pharmacodyn., 219, 149-159 (1976)). That is, compound (I) lowers fever in rats such as aspirin and acetaminophen.

Compound (I) can be used in the relief, treatment or prevention of pain (moderate to severe), inflammation or fever in mammals, including humans, such as headache, toothache, pain due to general dental procedures, oral or general surgery, menstrual cramps, muscle pain, cancer pain, diseases of the nervous system and peripheral nervous system, rheumatoid arthritis, ankylosing spondylitis, gout and other rheumatic conditions, fever and other conditions associated with pain, inflammation or fever.

The amount of active compound required for the above purposes, i.e. Compound (I), will, of course, vary with the mode of administration and the conditions of treatment as well as with the mammal being treated, but will ultimately be assessed by the attending physician. However, the analgesic, anti-inflammatory and / or antipyretic dose of the active compound in a mammal ranges from 3 to 120 mg per kilogram of body weight per day; the typical human dose is 15 mg per kilogram body weight per day.

The desired dose is preferably divided into 2 to 4 divided doses administered at appropriate intervals throughout the day. Thus, when the 35 doses are divided into three portions, each ranging from 3 70893 to 1 to 20 mg per kilogram of body weight, a typical human dose is 3 mg per kilogram of body weight.

Although it would be possible to administer the active compound as such as a crude product, it is preferable to administer the active compound as a pharmaceutical preparation. These preparations, for both veterinary and human use, consist of the active compound together with one or more pharmaceutically acceptable carriers and optionally further comprise another therapeutic agent. Carriers must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Other therapeutic agents may be other analgesics (such as codeine), anti-inflammatory or antipyretic agents.

The preparations include preparations suitable for oral, rectal or parenteral (including subcutaneous, intramuscular and intravenous) administration.

The preparations are conveniently presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general, the preparations are prepared by contacting the active compound throughout with a liquid or finely divided solid carrier, or both, and then, if necessary, shaping the product into the desired shape.

Formulations suitable for oral administration may be presented as discrete parts such as capsules, cachets, tablets, or lozenges, each containing a predetermined dose of the active ingredient as a powder or granules; or as a suspension in an aqueous or non-aqueous liquid such as a syrup, elixir, emulsion or group of drugs. The active compound may also be in the form of a clay, porridge or paste.

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A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active compound in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, surfactant or dispersant. Molded tablets may be made by molding in a suitable machine a mixture of the powdered active ingredient and a suitable carrier.

The syrup may be prepared by adding the active compound to a concentrated sugar solution, for example a sucrose solution, to which may be added any other additives. These additives include flavoring agents, sugar crystallization inhibitors, and agents that increase the solubility of other substances such as polyhydric alcohols, for example, glycerol or sorbitol.

Formulations for rectal administration may be as a suppository with a usual carrier such as cocoa butter.

In preparations suitable for parenteral administration, the active ingredient is usually in a sterile aqueous solution, which is preferably isotonic with the blood of the recipient.

In addition to the above, the preparations may contain one or more other additives such as diluents, buffers, flavoring agents, binders, surfactants, thickeners, lubricants, preservatives (including antioxidants), and so forth.

Compound (I) is prepared by any method known for preparing a compound having an analogous structure.

One process for the preparation of compound (I) comprises cyclizing a compound of formula (II) or formula (III) as described below: 70893

v <. O

X- (CH9) x Γ Λ o / CH 2

NH NH

'Φ,' 'lo-_CH2 0 -ch2 10 where X is a conventional leaving group (J. March, Advanced Organic Chemistry, 2nd Edition, page 187, New York (1977)) such as a halide, for example chloride or bromide hydroxide, R 2, imidazolyl, sulfoxonium or tosyl; and is hydrogen or alkyl of 1 to 4 carbon atoms, preferably ethyl. Preferred compounds of formula (II) are those in which the leaving group is a halide (such as chloride or bromide), hydroxide or tosyloxy, and preferred compounds of formula (III) are those in which the leaving group is -O 2 · * ·. Particularly preferred is a process for the cyclization of a compound of formula (II) as defined above, especially wherein X is chloride.

The cyclization can be carried out at room temperature or by heating, for example at 155-220 ° C, optionally in an oxygen-free atmosphere, for example nitrogen, optionally in an inert solvent such as tetrahydrofuran, dichloromethane, diethyl ether, tert-butanol, xylene or toluene and optionally in the presence of a catalyst. The choice of catalyst depends on the cyclizable compound of formula (I) or (II), for example if an acid such as hydrochloric acid is liberated in the reaction, a basic catalyst may be used with or without a solvent such as water or an alcohol such as butanol optionally but preferably in the presence of a phase transfer catalyst. such as triethylbenzylammonium chloride, which may be with or without a solvent such as dichloromethane, diethyl ether, xylenes or toluene, preferably dichloromethane. Examples of suitable basic catalysts are: alkali metal hydrides, hydroxide or alkoxide, potassium tert-butoxy-5 di or lithium diisopropylamide. The most preferred cyclization method uses an aqueous solution of sodium hydroxide in the presence of triethylbenzylammonium chloride at room temperature.

When X is a slow or difficult leaving group, ring-10 ringing can be performed by converting sc in situ to a second and better leaving group. For example, when X is a hydroxide, tosyl chloride may be present in the reaction mixture in order for the tosyloxy group (better leaving group) to replace the hydroxide group, whereby the cyclization takes place faster and more completely.

Compounds of formula (II) or (III) may be prepared by analogous methods known to those skilled in the art, for example by administering 3,4-methylenedioxyaniline (formula (V)):

Ti o-ch2 or a salt thereof such as an acid addition salt, which may be, for example, a hydrochloride, an alkali metal or alkaline earth metal salt such as a lithium salt, reacts with an internal ester, an acid halide, for example an acid chloride or an acid anhydride. For example, a compound of formula (V) may react with a compound of formula Cl- (CH2) -j-COCl to give a compound of formula (II) wherein X is chloride upon reaction in dimethoxyethane or dichloromethane in the presence of triethylamine.

The reaction can be carried out under the same or similar conditions as the cyclization described above, since the compound of formula (II) or (III) does not need to be isolated but can be cyclized in situ, for example by analogous methods described by A. Pernot and A. Willemart, Memoires Presentes a La Soc. Chim. 324 (1953); W.R. Schleigh, 5 A. Catala and F. D. Popp, J. Het. Chem., 2, 379 (1965); or I Badilescu Tetrahedron, 264 207 (1970).

Another method involves the reaction of 3,4- (methylenedioxy) aniline with tert-butyrolactone.

The following examples illustrate the present invention.

10 All temperatures are in degrees Celsius.

Example I: Preparation of 1- (1,3-benzodioxol-5-yl) -2-pyrrolidinone

Method A

A mixture of 3,4- (methylenedioxy) aniline (200 g, 1.46 moles) and β-butyrolactone (225 mL) was heated (in a dry nitrogen atmosphere) with stirring to 200 ° C in an oil bath for 2 days. The product was isolated from the reaction mixture by distillation under reduced pressure (boiling point 156 ° C, 33 μ). The product was filtered through Silica Gel 60 (trademark) eluting with ethyl acetate. The eluent was concentrated and the crystalline product was collected and washed with ether and petroleum ether to give 1- (1,3-benzodioxol-5-yl) -2-pyrrolidinone (153.4 g; 51%), m.p. a point of 89-91 ° C from which a single spot formed on the sheet. Elemental analysis: Calculated: C 18 H 18 NO 3 S 25 ° C, 64.38%; H 5.40 N, 6.83% Found: C, 64.30%; H 5.33%; N, 6.81%.

Method B

4-Chlorobutyryl chloride (1095.5 g, 7.77 moles) was added at 10-25 ° C to 3,4- (methylenedioxy) aniline 30 (1000.0 g, 7.29 moles), triethylamine (749.0 g, 7 , 40 moles) and methylene chloride (2500 mL). The mixture was stirred for 18 hours at ambient temperature, after which ether was added and the butyramide intermediate was filtered and then stirred in water. Methylene chloride (10 mL), a 50 wt% aqueous solution of sodium hydroxide (2000.0 g, 0.22 mol) was isolated from wet butyramide y-35. The mixture was stirred at ambient temperature for 2.5 hours, after which it was diluted with water and the aqueous layer was separated. The methylene chloride layer was washed with water, decolorized with Darco G-60 and Filtrol 19, after which the mixture was concentrated in vacuo. Ether was added to the concentrated solution. The mixture was cooled and the solid was collected and recrystallized from methylene chloride / ether to give 2245.0 g (75%) of product.

Example II: Analgesic Effect 10 A. Acetic Acid Writing Test (AAWT) Using the method described by Koster et al., Fed. Proc. 18,412 (1959) and Vinegar et al., Handbook of Experimental Pharmacology, 50-2, ch, 26, Anti-inflammatory Drugs, ed. J.R. Vane and S.H. Ferreira (1978), 15 acetic acid writing tests were performed on both mice and rats, thus demonstrating a mild analgesic effect of compound (I). The comparison results are shown in Table I.

Table I

Results of acetic acid typing test in rat Compound ED ^ ^ mg / kg, p.o.

Compound I 36-7.1

Acetaminophen 127-16.4

Aspirin 21 - 3.4

Codeine Phosphate 30 - 2.7 25 B. Modified Trypsin Hyperanalgesia (THA) Test This test measures analgesia quantitatively and is designed to be reliable even for compounds with anti-inflammatory activity. Vinegar'in et al., 30 Eur. Pharmacol, 37, 23 (1976), was used to demonstrate the analgesic effect of Compound (I) and some known analgesics. The analgesic agent was administered 30 minutes after trypsin administration. In addition, a modification of a test published by Vinegar was performed in which an analgesic agent was administered 15 minutes before trypsin injection (0.10 ml of a 10% solution of trypsin in pyrogen-free water). In both tests, pain scores were determined 60 minutes after trypsin injection. The purpose of the modification was to increase the sensitivity of the THA to the mild analgesic effect of the substances. Comparative results are shown in Table II. Compound (I) is found to be as active against a force of 7.5 kg as against a force of 6.0 kg, while acetaminophen is practically inactive at 7.5 kg.

Table II

10 Results of a modified trypsin hyperanalgesia test in the rat

Compound 6.0 kg force ED5Qmg / kg, p.o. 7.5 kg force

Compound I 24 - 5.3 23 - 3.5 Acetaminophen 95-17.2 I (3,200

Aspirin I |

Codeine phosphate_10 to 1.7_8.8 to 2.77_ I = inactive 20 rats were usually used at each dose level, and at least 3 dose levels were used.

C. Rat hot plate experiment

The rat hot plate experiment contained two variants compared to the original mouse hot plate experiment, described by Eddy et al., J. Pharmacol, Exp. Ther. 98, 121-137 (1950). The first modification was to expand the diameter of the cylindrical (water-filled) copper plate to 25.0 cm to fit the rat instead of the mouse. Another modification was the use of a temperature controller in an infrared heat lamp controlled by 30 heat sensors attached to the lower surface of the top of the copper plate. Thus, the surface temperature was maintained at 45-1.0 ° C (N = 28 measurements of hot plate temperature during the experiment). The time taken for a rat placed on a hot plate to react by either raising, shaking, or licking its front or hind limbs was recorded in tenths of a second. Only animals that responded for 6-13 seconds in the pre-tests were used in the studies. The drugs were suspended in 0.5% sodium carboxymethylcellulose and administered orally, by gavage, at a dose of 100.0 ml / 100 g body weight, 60 minutes before the test. Animals that reacted faster than 18.3 seconds were considered unprotected and those that did not respond in 18.3 seconds were considered protected. The reaction time of 18.3 seconds represents the average of the results obtained in the pretreatments for 40 untreated rats plus three standard-10 deviations from the mean. The ED 2 values and their standard deviations were estimated from a graphical dose-response curve using the method of Miller and Tainter (Proc.Soc.Exp. Biol.Med. 57, 261-262 (1944)). -15 steering wheel for the effects of conventional analgesics (Table III).

Table III

Results of the hot plate test 20 of formula (I)

Test compound Aspirin nofen Codeine Morphine

Hot plate test Rat ED 50 mg / kg 86 to 16.5 Inactivated Inactivated 57-35.3 17-3.6 oblique vines 25 p.o_360 in 360_

Moon plate duration of action * -Hrs 5.0 - - 3.3 3.5 (Dose-mg / kg 30 po) _ (120) _ (90) (30) * The duration of action in the rat hot plate test represents the time in hours , which is required to reduce the hot ED ED value of 1.5 times to 40% inhibition.

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Example III: Acute anti-inflammatory effect: Carrageenan pleurisy test (CPA)

Following Vinegar et al., Proc.Soc.Exp.Biol.Med. 5,151, 556 (1976), the acute anti-inflammatory effect of compound (I) was compared with that of known anti-inflammatory drugs in rats. The usual 3-hour oozing volume was determined for each drug-treated group, and 10% inhibition was calculated compared to solvent-fed control animals alone, with the ED 2 q being the dose required to reduce the 3-hour oozing volume by 50%.

Table IV

15 Results of the acute anti-inflammatory test (CPA)

All results are expressed as ED ^ q mg / kg, p.o.

Aspirin 28 - 3.2 20 Acetaminophen 172 - 22.4

Compound I 48-10.5

Example IV: Antipyretic effect in a yeast-induced fever test performed according to the method of Khalili et al. by the method described, Arch.Int.

Pharmacodyn.219, 149-159 (1976), showed the antipyretic effect of Compound (I) and some known antipyretic agents in the rat. The results are shown in Table V.

Table V: 30 Results of the antipyretic test All results are expressed as ED ^ q mg / kg

Test_Compound (I) _Aspirine_Asetaminophen

Rat yeast fever (p.o.) 67 - 4.2 50 - 8.1 72 - 8.6 70893

Example V: Toxicity The LD50 values of Compound (I) were found to be 2724 to 434 mg / kg orally in male and 2025 mg / kg (95% consistency) in female rats and 606 to mg / kg infraperitoneally. male rats and 770-4 mg / kg female rats. These are well above the therapeutic limit.

Claims (2)

13 70893 A process for the preparation of an analgesic, anti-inflammatory and antipyretic compound of formula (I) called 1- (1,3-benzodioxol-5-yl) -2-pyrrolidinone, O'nn '(I) 10 Φ »15 ° - ^ Η2 characterized in that a) a compound of formula (II) or formula (III) is cyclized X - (CH 2) 3 X - y / * 2 * 2 NH NH 4 ra '30 wherein X is a conventional leaving group, or b) reacting 3,4- (methylenedioxy) aniline with n-butyrolactone. Process according to Claim 1, characterized in that the compound of formula (II) or of formula 35 (III) in which X is a conventional leaving group is cyclized in the presence of an aqueous alkali, a metal hydride, hydroxide or alkoxide and a phase transfer catalyst.